Method and system for evaluating cardiac ischemia

ABSTRACT

A method of assessing cardiac ischemia in a subject to provide a measure of cardiovascular health in that subject is described herein. The method comprises the steps of: (a) collecting a first QT- and RR-interval data set from the subject during a stage of gradually increasing heart rate (e.g., a stage of gradually increasing exercise load); (b) collecting a second QT- and RR-interval data set from the subject during a stage of gradually decreasing heart rate (e.g., a stage of gradually decreasing exercise load); (c) comparing the first QT- and RR-interval data set to the second QT- and RR-interval data set to determine the difference between the data sets; and (d) generating from the comparison of step (c) a measure of cardiac ischemia during exercise in the subject. A greater difference between the first and second data sets indicates greater cardiac ischemia and lesser cardiovascular health in the subject. The data sets are collected in such a manner that they reflect almost exclusively the conduction in the heart muscle and minimize rapid transients due to autonomic nervous system and hormonal control on the data sets.

SUMMARY OF THE INVENTION

The present invention relates to non-invasive high-resolutiondiagnostics of cardiac ischemia based on processing of body-surfaceelectrocardiogram (ECG) data. The invention's quantitative method ofassessment of cardiac ischemia may simultaneously indicate both cardiachealth itself and cardiovascular system health in general.

BACKGROUND OF THE INVENTION

Heart attacks and other ischemic events of the heart are among theleading causes of death and disability in the United States. In general,the susceptibility of a particular patient to heart attack or the likecan be assessed by examining the heart for evidence of ischemia(insufficient blood flow to the heart tissue itself resulting in aninsufficient oxygen supply) during periods of elevated heart activity.Of course, it is highly desirable that the measuring technique besufficiently benign to be carried out without undue stress to the heart(the condition of which might not yet be known) and without unduediscomfort to the patient.

The cardiovascular system responds to changes in physiological stress byadjusting the heart rate, which adjustments can be evaluated bymeasuring the surface ECG R-R intervals. The time intervals betweenconsecutive R waves indicate the intervals between the consecutiveheartbeats (RR intervals). This adjustment normally occurs along withcorresponding changes in the duration of the ECG QT intervals, whichcharacterize the duration of electrical excitation of cardiac muscle andrepresent the action potential duration averaged over a certain volumeof cardiac muscle (FIG. 1). Generally speaking, an average actionpotential duration measured the QT interval at each ECG lead may beconsidered as an indicator of cardiac systolic activity varying in time.

Recent advances in computer technology have led to improvements inautomatic analyzing of heart rate and QT interval variability. It iswell known now that the QT interval's variability (dispersion)observations performed separately or in combination with heart rate (orRR-interval) variability analysis provides an effective tool for theassessment of individual susceptibility to cardiac arrhythmias (B.Surawicz, J. Cardiovasc. Electrophysiol, 1996, 7, 777-784). Applicationsof different types of QT and some other interval variability tosusceptibility to cardiac arrhythmias are described in Chamoun U.S. Pat.No. 5,020,540, 1991; Wang U.S. Pat. No. 4,870,974, 1989; Kroll et al.U.S. Pat. No. 5,117,834, 1992; Henkin et al. U.S. Pat. No. 5,323,783,1994; Xue et al. U.S. Pat. No. 5,792,065, 1998; Lander U.S. Pat. No.5,827,195, 1998; Lander et al. U.S. Pat. No. 5,891,047, 1999; Hojum etal. U.S. Pat. No. 5,951,484, 1999).

It was recently found that cardiac electrical instability can be alsopredicted by linking the QT-dispersion observations with the ECG T-wavealternation analysis (Verrier et al., U.S. Pat. Nos. 5,560,370;5,842,997; 5,921,940). This approach is somewhat useful in identifyingand managing individuals at risk for sudden cardiac death. The authorsreport that QT interval dispersion is linked with risk for arrhythmiasin patients with long QT syndrome. However, QT interval dispersionalone, without simultaneous measurement of T-wave alternation, is saidto be a less accurate predictor of cardiac electrical instability (U.S.Pat. No. 5,560,370 at column 6, lines 4-15).

Another application of the QT interval dispersion analysis forprediction of sudden cardiac death is developed by J. Sarma (U.S. Pat.No. 5,419,338). He describes a method of an autonomic nervous systemtesting that is designed to evaluate the imbalances between bothparasympathetic and sympathetic controls on the heart and, thus, toindicate a predisposition for sudden cardiac death.

The same author suggested that an autonomic nervous system testingprocedure might be designed on the basis of the QT hysteresis (J. Sarmaet al., PACE 10, 485-491 (1988)). Hysteresis between exercise andrecovery was observed, and was attributed to sympatho-adrenal activityin the early post-exercise period. Such an activity was revealed in thecourse of QT interval adaptation to changes in the RR interval duringexercise with rapid variation of the load.

The influence of sympatho-adrenal activity and the sharp dependence ofthis hysteresis on the time course of abrupt QT interval adaptation torapid changes in the RR interval dynamics radically overshadows themethod's susceptibility to the real ischemic-like changes of cardiacmuscle electrical parameters and cardiac electrical conduction.Therefore, this type of hysteresis phenomenon would not be useful inassessing the health of the cardiac muscle itself, or in assessingcardiac ischemia.

A similar sympatho-adrenal imbalance type hysteresis phenomenon wasobserved by A. Krahn et al. (Circulation 96, 1551-1556 (1997)(see FIG. 2therein)). The authors state that this type of QT interval hysteresismay be a marker for long-QT syndrome. However, long-QT syndromehysteresis is a reflection of a genetic defect of intracardiac ionchannels associated with exercise or stress-induced syncope or suddendeath. Therefore, similar to the example described above, although dueto two different reasons, it also does not involve a measure of cardiacischemia or cardiac muscle ischemic health.

A conventional non-invasive method of assessing coronary artery diseasesassociated with cardiac ischemia is based on the observation ofmorphological changes in a surface electrocardiogram duringphysiological exercise (stress test). A change of the ECG morphology,such as an inversion of the T-wave, is known to be a qualitativeindication of ischemia. The dynamics of the ECG ST-segments arecontinuously monitored while the shape and slope, as well as ST-segmentelevation or depression, measured relative to an average base line, arealtering in response to exercise load. A comparison of any of thesechanges with average values of monitored ST segment data provides anindication of insufficient coronary blood circulation and developingischemia. Despite a broad clinical acceptance and the availability ofcomputerized Holter monitor-like devices for automatic ST segment dataprocessing, the diagnostic value of this method is limited due to itslow sensitivity and low resolution. Since the approach is specificallyreliable primarily for ischemic events associated with relatively highcoronary artery occlusion, its widespread use often results in falsepositives, which in turn may lead to unnecessary and more expensive,invasive cardiac catheterization.

Relatively low sensitivity and low resolution, which are fundamentaldisadvantages of the conventional ST-segment depression method, areinherent in such method's being based on measuring an amplitude of abody surface ECG signal, which signal by itself does not accuratelyreflect changes in an individual cardiac cell's electrical parametersnormally changing during an ischemic cardiac event. A body surface ECGsignal is a composite determined by action potentials aroused fromdischarge of hundred of thousands of individual excitable cardiac cells.When electrical activity of excitable cells slightly and locally altersduring the development of exercise-induced local ischemia, itselectrical image in the ECG signal on the body surface is significantlyovershadowed by the aggregate signal from the rest of the heart.Therefore, regardless of physiological conditions, such as stress orexercise, conventional body surface ECG data processing is characterizedby a relatively high threshold (lower sensitivity) of detectableischemic morphological changes in the ECG signal. An accurate andfaultless discrimination of such changes is still a challenging signalprocessing problem.

Accordingly, an object of the present invention is to provide anon-invasive technique for detecting and measuring cardiac ischemia in apatient.

Another object of the invention is to provide a technique for detectingand measuring cardiac ischemia, which technique is not undulyuncomfortable or stressful for the patient.

Another object of the invention is to provide a technique for detectingand measuring cardiac ischemia, which technique can be implemented withrelatively simple equipment.

Still another object of the invention is to provide a technique fordetecting and measuring cardiac ischemia, which technique is sensitiveto low-level ischemic events.

SUMMARY OF THE INVENTION

The present invention overcomes the deficiencies in the conventionalST-segment analysis. Although still based on the processing of a bodysurface ECG signal, it nevertheless provides a highly sensitive and highresolution method for distinguishing changes in cardiac electricalconduction associated with developing ischemia. In addition to thesignificant ischemic changes detectable by the conventional method, thepresent invention allows one to determine much smaller ischemia-inducedconditions and alterations in cardiac electrical conduction. Thus,unlike a conventional ST-segment depression ischemic analysis, themethod of the present invention opens up opportunities to detect lowlevel cardiac ischemia (undetectable via the regular ST segment method)and also to resolve and monitor small variations of cardiac ischemia. Inparticular, individuals who would be considered of the same level ofcardiac and cardiovascular health according to a conventional ECGevaluation (an ST-depression method), will have different measurementsif compared according to the method of the present invention, and thecardiac and cardiovascular health of an individual can be quantitativelyevaluated, compared and monitored by repeated applications of the methodof the present invention.

The present invention is based in part on the discovery that, undercertain physiological conditions, QT- and RR-interval data sets may beinterpreted as representing composite dispersion-restitution curves,which characterize the basic dynamic properties of the medium (in thiscase, cardiac muscle). Indeed, if rapid QT interval adaptationfacilitated by sympatho-adrenal activity occurs much faster than gradualheart rate changes following slow alteration of external physiologicalconditions, then the QT interval may be considered primarily as afunction of a heart rate and/or a preceding cardiac cycle length anddoes not substantially depend on time-dependent sympatho-adrenaltransients. In such a case a particular QT- and RR-interval data setdetermines a time-independent, dispersion-like, quasi-stationary curvewhich does not substantially depend on rapid adaptational transients anddepends primarily on medium electrical parameters.

Based on this discovery, the present invention provides a highlysensitive and high resolution method of assessing cardiac ischemia. Thismethod allows one to detect comparatively small alterations of cardiacmuscle electrical excitation properties that develop during even amoderate ischemic event. For example, consider a gradual heart rateadjustment in a particular human subject in response to slow(quasi-stationary) there-and-back changes of external physiologicalconditions. Ideally, when a cardiac muscle is supplied by a sufficientamount of oxygen during both gradually increasing and graduallydecreasing heart rate stages, the corresponding, there-and-backquasi-stationary QT versus RR interval curves which result should bevirtually identical. However, if ischemia exists, even if only to a veryminor extent, there will be alterations of cardiac muscle repolarizationand excitation properties for the human subject with the result that oneobserves a specific quasi-stationary QT-RR hysteresis loop. Unlikenon-stationary loops (J. Sarma et al., supra (1987); A. Krahn et al.,supra (1997)), the quasi-stationary hystereses of the present inventiondo not vary substantially versus the course of sympatho-adrenalQT-interval adjustment. The domains and shapes of these loops are notsignificantly affected by time-dependent transients rapidly decayingduring a transition from one particular heart rate to another; instead,they depend primarily on ischemia-induced changes of medium parameters.The domain encompassed by such a quasi-stationary hysteresis loop andits shape represent a new quantitative characteristic that indicatescardiac muscle health itself and the health of cardiovascular system ingeneral. Moreover, any measure of the shape and/or domain enclosed inthe hysteresis loop (a measure of a set as defined in the integraltheory) possesses the property that any expansion of the domain resultsin an increase of the measure. Any such mathematical measure can betaken as the new characteristics of cardiac health mentioned above. Anarbitrary monotonic function of such a measure would still represent thesame measure in another, transformed scale.

A first aspect of the present invention is a method of assessing cardiacischemia in a subject to provide a measure of cardiovascular health inthat subject. The method comprises the steps of:

(a) collecting a first QT- and RR-interval data set from the subjectduring a stage of gradually increasing heart rate;

(b) collecting a second QT- and RR-interval data set from the subjectduring a stage of gradually decreasing heart rate;

(c) comparing said first QT- and RR-interval data set to the second QT-and RR-interval data set to determine the difference between the datasets; and

(d) generating from the comparison of step (c) a measure of cardiacischemia during exercise in said subject, wherein a greater differencebetween said first and second data sets indicates greater cardiacischemia and lesser cardiovascular health in said subject.

During the periods of gradually increasing and gradually decreasingheart rate the effect of the sympathetic, parasympathetic, and hormonalcontrol on formation of the hysteresis loop is sufficiently small,minimized or controlled so that the ischemic changes are readilydetectable. This maintenance is achieved by effecting a gradual increaseand gradual decrease in the heart rate, such as, for example, bycontrolling the heart rate through pharmacological intervention, bydirect electrical stimulation of the heart, or by gradually increasingand gradually decreasing exercise loads.

Accordingly, the foregoing method can be implemented in a variety ofdifferent ways. A particular embodiment comprises the steps of:

(a) collecting a first QT- and RR-interval data set from said subjectduring a stage of gradually increasing exercise load and graduallyincreasing heart rate;

(b) collecting a second QT- and RR-interval data set from said subjectduring a stage of gradually decreasing exercise load and graduallydecreasing heart rate;

(c) comparing the first QT- and RR-interval data set to the second QT-and RR-interval data set to determine the difference between said datasets; and

(d) generating from said comparison of step (c) a measure of cardiacischemia during exercise in said subject, wherein a greater differencebetween said first and second data sets indicates greater cardiacischemia and lesser cardiovascular health in said subject.

A second aspect of the present invention is a system for assessingcardiac ischemia in a subject to provide a measure of cardiovascularhealth in that subject. The system comprises:

(a) an ECG recorder for collecting a first QT- and RR-interval data setfrom the subject during a stage of gradually increasing heart rate andcollecting a second QT- and RR-interval data set from the subject duringa stage of gradually decreasing decreasing heart rate;

(b) a computer program running in a computer or other suitable means forcomparing said first QT- and RR-interval data set to the second QT- andRR-interval data set to determine the difference between the data sets;and

(c) a computer program running in a computer or other suitable means forgenerating from said determination of the difference between the datasets a measure of cardiac ischemia during exercise in said subject,wherein a greater difference between the first and second data setsindicates greater cardiac ischemia and lesser cardiovascular health inthe subject.

The present invention is explained in greater detail in the drawingsherein and the specification set forth below.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 is a schematic graphic representation of the action potential incardiac muscle summed up over its volume and the inducedelectrocardiogram (ECG) recorded on a human's body surface.

FIG. 2A depicts the equations used in a simplified mathematical model ofperiodic excitation.

FIG. 2B depicts a periodic excitation wave (action potential, u, andinstantaneous threshold, v, generated by computer using a simplifiedmathematical model, the equations of which are set forth in FIG. 2A.

FIG. 2C depicts a family of four composite dispersion-restitution curvescorresponding to four values of the medium excitation threshold.

FIG. 3 is a block diagram of an apparatus for carrying out the presentmethod.

FIG. 4A is a block diagram of the processing steps for data acquisitionand analysis of the present invention.

FIG. 4B is an alternative block diagram of the processing steps for dataacquisition and analysis of the present invention.

FIG. 5 illustrates experimental QT-interval versus RR-intervalhysteresis loops for two healthy male (23 year old, thick line and 47year old, thin line) subjects plotted on the compositedispersion-restitution curve plane.

FIG. 6 provides examples of the QT-RR interval hysteresis for two malesubjects, one with a conventional ECG ST-segment depression (thin line)and one with a history of a myocardial infarction 12 years prior to thetest (thick line). The generation of the curves is explained in greaterdetail in the specification below.

FIG. 7 illustrates sensitivity of the present invention and shows twoQT-RR interval hysteresis loops for a male subject, the first one (thicklines) corresponds to the initial test during which an ST-segmentdepression on a conventional ECG was observed, and the second one shownby thin lines measured after a period of regular exercise.

FIG. 8 illustrates a comparative ischemia analysis based on a particularexample of a normalized measure of the hysteresis loop area.<CII>=(CII−CII_(min))/(CII_(max)−CII_(min)) (“CII” means “cardiacischemia index”). O₁, X₁, and Y₁represent human subject data. X_(i)represents data collected from one subject (0.28-0.35) in a series oftests (day/night testing, run/walk, about two months between tests);exercise peak heart rate ranged from 120 to 135. Y_(i) represents datacollected from one subject (0.46-0.86) in a series of tests (run/walk,six weeks between tests before and after a period of regular exercisestage); exercise peak heart rate ranged from 122 to 146. Black barsindicate a zone (<CII> less than 0.70) in which a conventional STdepression method does not detect ischemia. The conventional method maydetect ischemia only in a significantly narrower range indicated by highwhite bars (Y₂, Y₃, O₇:<CII> greater than 0.70).

FIG. 9 illustrates a typical rapid peripheral nervous system andhormonal control adjustment of the QT and RR interval to an abrupt stopin exercise (that is, an abrupt initiation of a rest stage).

FIG. 10 illustrates a typical slow (quasi-stationary) QT and RR intervaladjustment measured during gradually increasing and gradually decreasingcardiac stimulation.

DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENT

The present invention is explained in greater detail below. Thisdescription is not intended to be a detailed catalog of all thedifferent manners in which particular elements of the invention can beimplemented, and numerous variations will be apparent to those skilledin the art based upon the instant disclosure.

1. Definitions

“Cardiac ischemia” refers to a lack of or insufficient blood supply to alocalized area of cardiac muscle. Cardiac ischemia usually occurs in thepresence of arteriosclerotic occlusion of a single or a group ofcoronary arteries. Arteriosclerosis is a product of a lipid depositionprocess resulting in fibro-fatty accumulations, or plaques, which growon the internal walls of coronary arteries. Such an occlusioncompromises blood flow through the artery, which reduction then impairsoxygen supply to the surrounding tissues during increased physiologicalneed—for instance, during increased exercise loads. In the later stagesof ischemia (e.g., significant coronary artery occlusion), the bloodsupply may be insufficient even while the cardiac muscle is at rest.However, in its earlier stages ischemia is reversible in a manneranalogous to how the cardiac muscle is restored to normal function whenthe oxygen supply to it returns to a normal physiological level. Thus,ischemia that may be detected by the present invention includes bothchronic and episodic (or “acute”) ischemia.

“Exercise” as used herein refers to voluntary skeletal muscle activityof a subject that increases heart rate above that found at a sustainedstationary resting state. Examples of exercise include, but are notlimited to, cycling, rowing, weight-lifting, walking, running,stair-stepping, etc., which may be implemented on a stationary devicesuch as a treadmill or in a non-stationary environment.

“Exercise load” or “load level” refers to the relative strenuousness ofa particular exercise, with greater loads or load levels for a givenexercise producing a greater heart rate in a subject. For example, loadmay be increased in weight-lifting by increasing the amount of weight;load may be increased in walking or running by increasing the speedand/or increasing the slope or incline of the walking or runningsurface; etc.

“Gradually increasing” and “gradually decreasing” an exercise loadrefers to exercise in which the subject is caused to perform an exerciseunder a plurality of different sequentially increasing or sequentiallydecreasing loads. The number of steps in the sequence can be infinite sothe terms gradually increasing and gradually decreasing loads includecontinuous load increase and decrease, respectively.

“Intervening rest”, when used to refer to a stage following increasedcardiac stimulation, refers to a stage of time initiated by asufficiently abrupt decrease in heart stimulation (e.g., an abruptdecrease in exercise load) so that it evokes a clear sympatho-adrenalresponse. Thus, an intervening rest stage is characterized by a rapidsympatho-adrenal adjustment (as further described in Example 8 below),and the inclusion of an intervening rest stage precludes the use of aquasi-stationary exercise (or stimulation) protocol (as furtherdescribed in Example 9 below).

“Hysteresis” refers to a lagging of the physiological effect when theexternal conditions are changed.

“Hysteresis curves” refer to a pair of curves in which one curvereflects the response of a system to a first sequence of conditions,such as gradually increasing heart rate, and the other curve reflectsthe response of a system to a second sequence of conditions, such asgradually decreasing heart rate. Here both sets of conditions areessentially the same—i.e., consist of the same (or approximately thesame) steps—but are passed in different order in the course of time. A“hysteresis loop” refers to a loop formed by the two contiguous curvesof the pair.

“Electrocardiogram” or “ECG” refers to a continuous or sequential record(or a set of such records) of a local electrical potential fieldobtained from one or more locations outside the cardiac muscle. Thisfield is generated by the combined electrical activity (action potentialgeneration) of multiple cardiac cells. The recording electrodes may beeither subcutaneously implanted or may be temporarily attached to thesurface of the skin of the subject, usually in the thoracic region. AnECG record typically includes the single-lead ECG signal that representsa potential difference between any two of the recording sites includingthe site with a zero or ground potential.

“Quasi-stationary conditions” refer to a gradual change in the externalconditions and/or the physiological response it causes that occurs muchslower than any corresponding adjustment due tosympathetic/parasympathetic and hormonal control. If the representativetime of the external conditions variation is denoted by τ_(ext), andτ_(int) is a representative time of the fastest of the internal,sympathetic/parasympathetic and hormonal control, then “quasi-stationaryconditions” indicates τ_(ext)>>τ_(int) (e.g., τ_(ext) is at least aboutfive times greater than τ_(int)). “An abrupt change” refers to anopposite situation corresponding a sufficiently fast change in theexternal conditions as compared with the ratesympathetic/parasympathetic and hormonal control, that is it requiresthat τ_(ext)<<τ_(int) (e.g., τ_(ext) is at least about five times lessthan τ_(int)). In particular, “an abrupt stop” refers to a fast removalof the exercise load that occurs during time shorter than τint˜20 or 30seconds (see FIG. 9 below and comments therein).

“QT- and RR-data set” refers to a record of the time course of anelectrical signal comprising action potentials spreading through cardiacmuscle. Any single lead ECG record incorporates a group of threeconsecutive sharp deflections usually called a QRS complex and generatedby the propagation of the action potential's front through theventricles. In contrast, the electrical recovery of ventricular tissueis seen on the ECG as a relatively small deflection known as the T wave.The time interval between the cardiac cycles (e.g., maxima of theconsecutive R-waves) is called an RR-interval, while the actionpotential duration (e.g., the time between the beginning of a QRScomplex and the end of the ensuing T-wave) is called a QT-interval.Alternative definitions of these intervals can be equivalently used inthe framework of the present invention. For example, an RR-interval canbe defined as the time between any two similar points, such as thesimilar inflection points, on two consecutive R-waves, or any other wayto measure cardiac cycle length. A QT-interval can be defined as thetime interval between the peak of the Q-wave and the peak of the T wave.It can also be defined as the time interval between the beginning (orthe center) of the Q-wave and the end of the ensuing T-wave defined asthe point on the time axis (the base line) at which it intersects withthe linear extrapolation of the T-wave's falling branch and started fromits inflection point, or any other way to measure action potentialduration. An ordered set of such interval durations simultaneously withthe time instants of their beginnings or ends which are accumulated on abeat to beat basis or on any given beat sampling rate basis form acorresponding QT- and RR-interval data set. Thus, a QT- and RR-intervaldata set will contain two QT-interval related sequences {T_(QT,1),T_(QT,2), . . . ,T_(QT,n),} and {t₁,t₂, . . . ,t_(n)}, and will alsocontain two RR-interval related sequences {T_(RR,1),T_(RR,2), . . .,T_(RR,n),} and {t₁, t₂, . . . ,t_(n)} (the sequence {t₁,t₂, . . .,t_(n)} may or may not exactly coincide with the similar sequence in theQT data set).

2. Dispersion/restitution Curves

FIG. 1 illustrates the correspondence between the temporal phases of theperiodic action potential (AP, upper graph, 20) generated inside cardiacmuscle and summed up over its entire volume and the electrical signalproduced on the body surface and recorded as an electrocardiogram (ECG,lower graph, 21). The figure depicts two regular cardiac cycles. Duringthe upstroke of the action potential the QRS-complex is formed. Itconsists of three waves, Q, R, and S, which are marked on the lowerpanel. The recovery stage of the action potential is characterized byits fall off on the AP plot and by the T-wave on the ECG plot. One cansee that the action potential duration is well represented by the timebetween Q and T waves and is conventionally defined as the QT interval,measured from the beginning of the Q wave to the end of the following Twave. The time between consecutive R-waves (RR interval) represents theduration of a cardiac cycle, while its reciprocal value represents thecorresponding instantaneous heart rate.

FIG. 2 illustrates major aspects of the process of propagation of aperiodic action potential through cardiac tissue and the formation of acorresponding composite dispersion-restitution curve. The tissue can beconsidered as a continuous medium and the propagation process as arepetition at each medium point of the consecutive phases of excitationand recovery. The former phase is characterized by a fast growth of thelocal membrane potential (depolarization), and the latter by its returnto a negative resting value (repolarization). The excitation phaseinvolves a very fast (˜0.1 ms) decrease in the excitation threshold andthe following development of a fast inward sodium current that causesthe upstroke of the action potential (˜1 ms). Next, during anintermediate plateau phase (˜200 ms) sodium current is inactivated,calcium and potassium currents are developing while the membrane istemporarily unexcitable (i.e., the threshold is high). During the nextrecovery phase (˜100 ms), a potassium current repolarizes the membraneso it again becomes excitable (the excitation threshold is lowered). Thecomplicated description of a multitude of ionic currents involved in theprocess can be circumvented if one treats the process directly in termsof the local membrane potential, u, and a local excitation threshold, v.Such a mathematical description referred to as the CSC model, wasdeveloped by Chernyak, Starobin, & Cohen (Phys. Rev. Lett., 80, pp.5675-5678, 1998) and is presented as a set of two Reaction-Diffusion(RD) equations in panel A. The left hand side of the first equationdescribes local accumulation of the electric charge on the membrane, thefirst term in the right hand side describes Ohmic coupling betweenneighboring points of the medium, and the term i(u, v) represents thetransmembrane current as a function of the membrane potential and thevarying excitation threshold (ε is a small constant, the ratio of theslow recovery rate to the fast excitation rate). A periodic solution (awave-train) can be found analytically for some particular functions i(u,v) and g(u, v). The wave-train shown in panel B has been calculated forg(u,v)=ζu+v_(r)-v, where ζ and v_(r) are appropriately chosen constants(v_(r) has the meaning of the initial excitation threshold and is themain determinant of the medium excitability). The function i(u,v) waschosen to consist of two linear pieces, one for the sub-thresholdregion, u<v, and one for supra-threshold region, u>v. That isi(u,v)=λ_(r)u when u≦v, and i(u,v)=λ_(ex)(u-u_(ex)) when u>v, whereλ_(r) and λ_(ex) are membrane chord conductances in the resting (u=0)and excited (u=u_(ex)) states, respectively. The resting state u=0 istaken as the origin of the potential scale. We used such units thatλ_(ex)=1 and u_(ex)=1. (For details see Chernyak & Starobin, CriticalReviews in Biomed. Eng. 27, 359-414 (1999)).

A medium with higher excitability, corresponding to the tissue withbetter conduction, gives rise to a faster, more robust action potentialwith a longer Action Potential Duration (APD). This also means that alonger lasting excitation propagates faster. Similarly, a wave trainwith a higher frequency propagates slower since the medium has less timeto recover from the preceding excitation and thus has a lower effectiveexcitability. These are quite generic features that are incorporated inthe CSC model. In physics, the relation between the wave's speed, c, andits frequency, f or its period, T=1/f, is called a dispersion relation.In the CSC model the dispersion relation can be obtained in an explicitform T=F_(T)(c), where F_(T) is a known function of c and the mediumparameters. The CSC model also allows us to find a relation between thepropagation speed and the APD, T_(AP), in the explicit formT_(AP)=F_(AP)(c), which represents the restitution properties of themedium. In the medical literature, the restitution curve is T_(AP)versus diastolic interval T_(DI), which differently makes a quitesimilar physical statement. One can consider a pair of dispersion andrestitution relations {T=F_(T)(c),T_(AP)=F_(AP)(c)} as a parametricrepresentation of a single curve on the (T,T_(AP))-plane as shown inpanel C (FIG. 2). Such a curve (relation) shall be referred to as acomposite dispersion-restitution curve (relation) and can be directlyobtained from an experimental ECG recording by determining the QT-RRinterval data set and plotting T_(QT) versus T_(RR). A condition thatthe experimental {T_(QT),T_(RR)} data set indeed represents thecomposite dispersion-restitution relation is the requirement that thedata are collected under quasi-stationary conditions. Understanding thisfact is a key discovery for the present invention.

3. Testing methods

The methods of the present invention are primarily intended for thetesting of human subjects. Any human subject can be tested by themethods of the present invention, including male, female, juvenile,adolescent, adult, and geriatric subjects. The methods may be carriedout as an initial screening test on subjects for which no substantialprevious history or record is available, or may be carried out on arepeated basis on the same subject (particularly where a comparativequantitative indicium of an individual's cardiac health over time isdesired) to assess the effect or influence of intervening events and/orintervening therapy on that subject between testing sessions.

As noted above, the method of the present invention generally comprises(a) collecting a first QT- and RR-interval data set from said subjectduring a stage of gradually increasing heart rate; (b) collecting asecond QT- and RR-interval data set from said subject during a stage ofgradually decreasing heart rate; (c) comparing said first QT- andRR-interval data set to said second QT- and RR-interval data set todetermine the difference between said data sets; and (d) generating fromsaid comparison of step (c) a measure of cardiac ischemia in thesubject. A greater difference between the first and second data setsindicates greater cardiac ischemia and lesser cardiovascular health inthat subject.

The stages of gradually increasing and gradually decreasing heart rateare carried out in a manner that maintains during both periodsessentially or substantially the same stimulation of the heart by theperipheral nervous and hormonal control systems, so that it is theeffect of cardiac ischemia rather than that of the external controlwhich is measured by means of the present invention. This methodologycan be carried out by a variety of techniques, with the technique ofconducting two consecutive stages of gradually increasing and graduallydecreasing exercise loads (or average heart rates) being currentlypreferred.

The stage of gradually increasing exercise load (or increased averageheart rate) and the stage of gradually decreasing exercise load (ordecreased average heart rate) may be the same in duration or may bedifferent in duration. In general, each stage is at least 3, 5, 8, or 10minutes or more in duration. Together, the duration of the two stagesmay be from about 6, 10, 16 or 20 minutes in duration to about 30, 40,or 60 minutes in duration or more. The two stages are preferably carriedout sequentially in time—that is, with one stage following after theother substantially immediately, without an intervening rest stage. Inthe alternative, the two stages may be carried out separately in time,with an intervening “plateau” stage (e.g., of from 1 to 5 minutes)during which cardiac stimulation or exercise load is held substantiallyconstant, before the stage of decreasing load is initiated.

The exercise protocol may include the same or different sets of loadsteps during the stages of increasing or decreasing heart rates. Forexample, the peak load in each stage may be the same or different, andthe minimum load in each stage may be the same or different. In general,each stage consists of at least two or three different load levels, inascending or descending order depending upon the stage. Relatively highload levels, which result in relatively high heart rates, can be usedbut are not essential. An advantage of the present invention is that itssensitivity allows both exercise procedures to be carried out atrelatively low load levels that do not unduly increase the pulse rate ofthe subject. For example, the method may be carried out so that theheart rate of the subject during either the ascending or descendingstage (or both) does not exceed about 140, 120, or even 100 beats perminute, depending upon the condition of the subject. Of course, datacollected at heart rates above 100, 120, or 140 beats per minute mayalso be utilized if desired, again depending upon the condition of thesubject.

For example, for an athletic or trained subject, for the first orascending stage, a first load level may be selected to require a poweroutput of 60 to 100 or 150 watts by the subject; an intermediate loadlevel may be selected to require a power output of 100 to 150 or 200watts by the subject; and a third load level may be selected to requirea power output of 200 to 300 or 450 watts or more by the subject. Forthe second or descending stage, a first load level may be selected torequire a power output of 200 to 300 or 450 watts or more by thesubject; an intermediate or second load level may be selected to requirea power output of 100 to 150 or 200 watts by the subject; and a thirdload level may be selected to require a power output of 60 to 100 or 150watts by the subject. Additional load levels may be included before,after, or between all of the foregoing load levels as desired, andadjustment between load levels can be carried out in any suitablemanner, including step-wise or continuously.

In a further example, for an average subject or a subject with a historyof cardiovascular disease, for the first or ascending stage, a firstload level may be selected to require a power output of 40 to 750 or 100watts by the subject; an intermediate load level may be selected torequire a power output of 75 to 100 or 150 watts by the subject; and athird load level may be selected to require a power output of 125 to 200or 300 watts or more by the subject. For the second or descending stage,a first load level may be selected to require a power output of 125 to200 or 300 watts or more by the subject; an intermediate or second loadlevel may be selected to require a power output of 75 to 100 or 150watts by the subject; and a third load level may be selected to requirea power output of 40 to 75 or 100 watts by the subject. As before,additional load levels may be included before, after, or between all ofthe foregoing load levels as desired, and adjustment between load levelscan be carried out in any suitable manner, including step-wise orcontinuously.

The heart rate may be gradually increased and gradually decreased bysubjecting the patient to a predetermined schedule of stimulation. Forexample, the patient may be subjected to a gradually increasing exerciseload and gradually decreasing exercise load, or gradually increasingelectrical stimulation and gradually decreasing electrical stimulation,according to a predetermined program or schedule. Such a predeterminedschedule is without feedback of actual heart rate from the patient. Inthe alternative, the heart rate of the patient may be graduallyincreased and gradually decreased in response to actual heart rate datacollected from concurrent monitoring of said patient. Such a system is afeedback system. For example, the heart rate of the patient may bemonitored during the test and the exercise load (speed and/or incline,in the case of a treadmill) can be adjusted so that the heart ratevaries in a prescribed way during both stages of the test. Themonitoring and control of the load can be realized by a computer orother control system using a simple control program and an output panelconnected to the control system and to the exercise device thatgenerates an analog signal to the exercise device. One advantage of sucha feedback system is that (if desired) the control system can insurethat the heart rate increases substantially linearly during the firststage and decreases substantially linearly during the second stage.

The generating step (d) may be carried out by any suitable means, suchas by generating curves from the data sets (with or without actuallydisplaying the curves), and then (i) directly or indirectly evaluating ameasure (e.g., as defined in the integral theory) of the domain (e.g.,area) between the hysteresis curves, a greater measure indicatinggreater cardiac ischemia in said subject, (ii) directly or indirectlycomparing the shapes (e.g., slopes) of the curves, with a greaterdifference in shape indicating greater cardiac ischemia in the subject;or (iii) combinations of (i) and (ii). Specific examples are given inExample 4 below.

The method of the invention may further comprise the steps of (e)comparing the measure of cardiac ischemia during exercise to at leastone reference value (e.g., a mean, median or mode for the quantitativeindicia from a population or subpopulation of individuals) and then (f)generating from the comparison of step (e) at least one quantitativeindicium of cardiovascular health for said subject. Any suchquantitative indicium may be generated on a one-time basis (e.g., forassessing the likelihood that the subject is at risk to experience afuture cardiac incident such as myocardial infarction or ventriculartachycardia), or may be generated to monitor the progress of the subjectover time, either in response to a particular prescribed cardiovasculartherapy, or simply as an ongoing monitoring of the physicial conditionof the subject for improvement or decline (again, specific examples aregiven in Example 4 below). In such a case, steps (a) through (f) aboveare repeated on at least one separate occasion to assess the efficacy ofthe cardiovascular therapy or the progress of the subject. A decrease inthe difference between said data sets from before said therapy to aftersaid therapy, or over time, indicates an improvement in cardiac healthin said subject from said cardiovascular therapy. Any suitablecardiovascular therapy can be administered, including but not limited toaerobic exercise, muscle strength building, change in diet, nutritionalsupplement, weight loss, smoking cessation, stress reduction,pharmaceutical treatment (including gene therapy), surgical treatment(including both open heart and closed heart procedures such as bypass,balloon angioplasy, catheter ablation, etc.) and combinations thereof.

4. Testing Apparatus.

FIG. 3 provides an example of the apparatus for data acquisition,processing and analysis by the present invention. Electrocardiograms arerecorded by an ECG recorder 30, via electrical leads placed on asubject's body. The ECG recorder may be, for example, a standardmulti-lead Holter recorder or any other appropriate recorder. Theanalog/digital converter 31 digitizes the signal recorded by the ECGrecorder and transfers them to a personal computer 32, or other computeror central processing unit, through a standard external input/outputport. The digitized ECG data can then be processed by standardcomputer-based waveform analyzer software. Compositedispersion-restitution curves and a cardiac or cardiovascular healthindicium or other quantitative measure of the presence, absence ordegree of cardiac ischemia can then be calculated automatically in thecomputer through a program (e.g., Basic, Fortran, C++, etc.) implementedtherein as software, hardware, or both hardware and software.

FIG. 4A and FIG. 4B illustrate the major steps of digitized dataprocessing in order to generate the comparison of QT-RR data setcollected from a subject during there-and-back quasi-stationary changesin physiological conditions. The first four steps in FIG. 4A and FIG. 4Bare substantially the same. The digitized data collected from amulti-lead recorder are stored in a computer memory for each lead as adata array 40 a, 40 b. The size of each data array is determined by thedurations of the ascending and descending heart rate stages and asampling rate used by the waveform analyzer, which processes an incomingdigitized ECG signal. The waveform analyzer software first detects majorcharacteristic waves (Q,R,S and T waves) of the ECG signal in eachparticular lead 41 a, 41 b. Then in each ECG lead it determines the timeintervals between consecutive R waves and the beginning of Q and the endof T waves 42 a, 42 b. Using these reference points it calculates heartrate and RR and QT intervals. Then, the application part of the softwaresorts the intervals for the ascending and descending heart rate stages43 a, 43 b. The next two steps can be made in one of the two alternativeways shown in FIGS. 4A and 4B, respectively. The fifth step as shown inFIG. 4A consists of displaying by the application part of software QTintervals versus RR-intervals 44 a, separately for the ascending anddescending heart rate stages effected by there-and-back gradual changesin physiological conditions such as exercise, pharmacological/electricalstimulation, etc. The same part of the software performs the next step45 a, which is smoothing, filtering or data fitting, using exponentialor any other suitable functions, in order to obtain a sufficientlysmooth curve T_(QT)=F(T_(RR)) for each stage. An alternative for thelast two steps shown in FIG. 4B requires that the application part ofthe software first averages, and/or filters and/or fits, usingexponential or any other suitable functions, the QT intervals asfunctions of time for both stages and similarly processes theRR-interval data set to produce two sufficiently smooth curvesT_(QT)=F_(QT)(t) and T_(RR)=F_(RR)(t), each including the ascending anddescending heart rate branches 44 b. At the next step 45 b theapplication part of the software uses this parametric representation toeliminate time and generate and plot a sufficiently smooth hysteresisloop T_(QT)=F(T_(RR)). The following steps shown in FIGS. 4A and FIG. 4Bare again substantially the same. The next step 46 a, 46 b performed bythe application part of the software can be graphically presented asclosing the two branch hysteresis loop with an appropriate line, such asa vertical straight line or a line connecting the initial and finalpoints, in order to produce a closed hysteresis loop on the(T_(QT),T_(RR))-plane. At the next step 47 a, 47 b the applicationsoftware evaluates for each ECG lead an appropriate measure of thedomain inside the closed hysteresis loop. A measure, as defined inmathematical integral theory, is a generalization of the concept of anarea and may include appropriate weight functions increasing ordecreasing the contribution of different portions of the domain intosaid measure. The final step 48 a, 48 b of the data processing for eachECG lead is that the application software calculates indexes byappropriately renormalizing the said measure or any monotonous functionsof said measure. The measure itself along with the indexes may reflectboth the severity of the exercise-induced ischemia, as well as apredisposition to local ischemia that can be reflected in someparticularities of the shape of the measured compositedispersion-restitution curves. The results of all above-mentioned signalprocessing steps may be used to quantitatively assess cardiac ischemiaand, as a simultaneous option, cardiovascular system health of aparticular individual under test.

Instead of using the (T_(QT),T_(RR))-plane a similar data processingprocedure can equivalently be performed on any plane obtained by anon-degenerate transformation of the (T_(QT),T_(RR))-plane, such as(T_(QT),f_(RR)) where f_(RR)=1/T_(RR) is the heart rate or the like.Such a transformation can be partly or fully incorporated in theappropriate definition of the said measure.

The present invention is explained in greater detail in the non-limitingexamples set forth below.

EXAMPLE 1 Testing Apparatus

A testing apparatus consistent with FIG. 3 was assembled. Theelectrocardiograms are recorded by an RZ152PM12 Digital ECG HolterRecorder (ROZINN ELECTRONICS, INC.; 71-22 Myrtle Av., Glendale, N.Y.,USA 11385-7254), via 12 electrical leads with Lead-Lok Holter/StressTest Electrodes LL510 (LEAD-LOK, INC.; 500 Airport Way, P.O.Box L,Sandpoint, Id., USA 83864) placed on a subject's body in accordance withthe manufacturer's instructions. Digital ECG data are transferred to apersonal computer (Dell Dimension XPS T500 MHz/Windows 98) using a 40 MBflash card (RZFC40) with a PC 700 flash card reader, both from RozinnElectronics, Inc. Holter for Windows (4.0.25) waveform analysis softwareis installed in the computer, which is used to process data by astandard computer based waveform analyzer software. Compositedispersion-restitution curves and an indicium that provides aquantitative characteristic of the extent of cardiac ischemia are thencalculated manually or automatically in the computer through a programimplemented in Fortran 90.

Experimental data were collected during an exercise protocol programmedin a Landice L7 Executive Treadmill (Landice Treadmills; 111 CanfieldAv., Randolph, N.J. 07869). The programmed protocol included 20step-wise intervals of a constant exercise load from 48 seconds to 1.5minutes each in duration. Altogether these intervals formed twoequal-in-duration gradually increasing and gradually decreasing exerciseload stages, with total duration varying from 16 to 30 minutes. For eachstage a treadmill belt speed and elevation varied there-and-back,depending on the subject's age and health conditions, from 1.5 miles perhour to 5.5 miles per hour and from one to ten degrees of treadmillelevation, respectively.

EXAMPLES 2-6 Human Hysteresis Curve Studies

These examples illustrate quasi-stationary ischemia-induced QT-RRinterval hystereses in a variety of different human subjects. These datademonstrate a high sensitivity and the high resolution of the method.

EXAMPLES 2-3 Hysteresis Curves in Healthy Male Subjects of DifferentAges

These examples were carried out on two male subjects with an apparatusand procedure as described in Example 1 above. Referring to FIG. 5, onecan readily see a significant difference in areas of hystereses betweentwo generally healthy male subjects of different ages. These subjects(23 and 47 years old) exercised on a treadmill according to aquasi-stationary 30-minute protocol with gradually increasing andgradually decreasing exercise load. Here squares and circles (thickline) indicate a hysteresis loop for the 23 year old subject, anddiamonds and triangles (thin line) correspond to a larger loop for the47 year old subject. Fitting curves are obtained using the third-orderpolynomial functions. A beat sampling rate with which a waveformanalyzer determines QT and RR intervals is equal to one sample perminute. Neither of the subjects had a conventional ischemia-induceddepression of the ECG-ST segments. However, the method of the presentinvention allows one to observe ischemia-induced hystereses that providea satisfactory resolution within a conventionally sub-threshold range ofischemic events and allows one to quantitatively differentiate betweenthe hystereses of the two subjects.

EXAMPLES 4-5 Hysteresis Curves for Subjects with ST Segment Depressionor Prior Cardiac Infarction

These examples were carried out on two 55 year old male subjects with anapparatus and procedure as described in Example 1 above. FIG. 6illustrates quasi-stationary QT-RR interval hystereses for the malesubjects. The curves fitted to the squares and empty circles relate tothe first individual and illustrate the case of ischemia also detectableby the conventional ECG-ST segment depression technique. The curvesfitted to the diamonds and triangles relate to the other subject, anindividual who previously had experienced a myocardial infarction. Thesesubjects exercised on a treadmill according to a quasi-stationary20-minute protocol with a gradually increasing and gradually decreasingexercise load. Fitting curves are obtained using third-order polynomialfunctions. These cases demonstrate that the method of the presentinvention allows one to resolve and quantitatively characterize thedifference between (1) levels of ischemia that can be detected by theconventional ST depression method, and (2) low levels of ischemia(illustrated in FIG. 5) that are subthreshold for the conventionalmethod and therefore undetectable by it. The levels of exercise-inducedischemia reported in FIG. 5 are significantly lower than those shown inFIG. 6. This fact illustrates insufficient resolution of a conventionalST depression method in comparison with the method of the presentinvention.

EXAMPLE 6 Hysteresis Curves in the Same Subject Before and After aRegular Exercise Regimen

This example was carried out with an apparatus and procedure asdescribed in Example 1 above. FIG. 7 provides examples ofquasi-stationary hystereses for a 55 year-old male subject before andafter he engaged in a practice of regular aerobic exercise. Bothexperiments were performed according to the same quasi-stationary20-minute protocol with a gradually increasing and gradually decreasingexercise load. Fitting curves are obtained using third-order polynomialfunctions. The first test shows a pronounced exercise-induced ischemicevent developed near the peak level of exercise load, detected by boththe method of the present invention and a conventional ECG-ST depressionmethod. The maximum heart rate reached during the first test (before aregular exercise regimen was undertaken) was equal to 146. After acourse of regular exercise the subject improved his cardiovascularhealth, which can be conventionally roughly, qualitatively, estimated bya comparison of peak heart rates. Indeed, the maximum heart rate at thepeak exercise load from the first experiment to the second decreased by16.4%, declining from 146 to 122. A conventional ST segment method alsoindicates the absence of ST depression, but did not provide anyquantification of such an improvement since this ischemic range issub-threshold for the method. Unlike such a conventional method, themethod of the present invention did provide such quantification.Applying the current invention, the curves in FIG. 7 developed from thesecond experiment show that the area of a quasi-stationary, QT-RRinterval hysteresis decreased significantly from the first experiment,and such hysteresis loop indicated that some level of exercise-inducedischemia still remained. A change in the shape of the observed compositedispersion-restitution curves also indicates an improvement since itchanged from a flatter curves, similar to the flatter curves (with alower excitability and a higher threshold, v_(r)=0 to 0.35) in FIG. 2,to a healthier (less ischemic) more convex-shape curve, which is similarto the lower threshold curves (v_(r)=0.2 to 0.25) in FIG. 2. Thus, FIG.7 demonstrates that, due to its high sensitivity and high resolution,the method of the present invention can be used in the assessment ofdelicate alterations in levels of cardiac ischemia, indicating changesof cardiovascular health when treated by a conventional cardiovascularintervention.

EXAMPLE 7 Calculation of a Quantitative Indicium of CardiovascularHealth

This example was carried out with the data obtained in Examples 2-6above. FIG. 8 illustrates a comparative cardiovascular health analysisbased on ischemia assessment by the method of the present invention. Inthis example an indicium of cardiovascular health (here designated thecardiac ischemia index and abbreviated “CII”) was designed, which wasdefined as a quasi-stationary QT-RR interval hysteresis loop area, S,normalized by dividing it by the product(T_(RR,max)−T_(RR,min))(T_(QT,max)−T_(QT,min)). For each particularsubject this factor corrects the area for individual differences in theactual ranges of QT and RR intervals occurring during the tests underthe quasi-stationary treadmill exercise protocol. We determined minimumand maximum CII in a sample of fourteen exercise tests and derived anormalized index <CII>=(CII−CII_(min))/(CII_(max)−CII_(min)) varyingfrom 0 to 1. Alterations of <CUI> in different subjects show that themethod of the present invention allows one to resolve and quantitativelycharacterize different levels of cardiac and cardiovascular health in aregion in which the conventional ST depression method is sub-thresholdand unable to detect any exercise-induced ischemia. Thus, unlike a roughconventional ST-segment depression ischemic evaluation, the method ofthe present invention offers much more accurate assessing and monitoringof small variations of cardiac ischemia and associated changes ofcardiovascular health.

EXAMPLE 8 Illustration of Rapid Sympatho-Adrenal Transients

FIG. 9 illustrates a typical rapid sympathetic/parasympathetic nervousand hormonal adjustment of the QT (panels A, C) and RR (panels B,D)intervals to an abrupt stop after 10 minutes of exercise with increasingexercise load. All panels depict temporal variations of QT/RR intervalsobtained from the right precordial lead V3 of the 12-lead multi-leadelectrocardiogram. A sampling rate with which a waveform analyzerdetermined QT and RR intervals was equal to 15 samples per minute. Ahuman subject (a 47 years-old male) was at rest the first 10 minutes andthen began to exercise with gradually (during 10 minutes) increasingexercise load (Panels A, B—to the left from the RR, QT minima). Then atthe peak of the exercise load (heart rate about 120 beat/min) thesubject stepped off the treadmill in order to initialize the fastest RRand QT interval's adaptation to a complete abrupt stop of the exerciseload. He rested long enough (13 minutes) in order to insure that QT andRR intervals reached post-exercise average stationary values. Panels Cand D demonstrate that the fastest rate of change of QT and RR intervalsoccurred immediately after the abrupt stop of the exercise load. Theserates are about 0.05 s/min for QT intervals while they vary from 0.28 sto 0.33 s and about 0.34 s/min for RR intervals while they grow from0.45 s to 0.79 s. Based on the above-described experiment, a definitionfor “rapid sympatho-adrenal and hormonal transients” or “rapid autonomicnervous system and hormonal transients” may be given.

Rapid transients due to autonomic nervous system and hormonal controlrefer to the transients with the rate of 0.5 s/min for RR intervals,which corresponds to the heart rate's rate of change of about 60beat/min, and 0.05 s/min for QT intervals or faster rates of change inRR/QT intervals in response to a significant abrupt change (stop orincrease) in exercise load (or other cardiac stimulus). The significantabrupt changes in exercise load are defined here as the load variationswhich cause rapid variations in RR/QT intervals, comparable in size withthe entire range from the exercise peak to the stationary average restvalues.

EXAMPLE 9 Illustration of a Quasi-Stationary Exercise Protocol

FIG. 10 illustrates a typical slow (quasi-stationary) QT (panel A) andRR (panel B) interval adjustment measured during gradually increasingand gradually decreasing exercise load in a right pre-cordial V3 lead ofthe 12 lead electrocardiogram recording. The sampling was 15 QT and RRintervals per minute. A male subject exercised during two consecutive 10minute long stages of gradually increasing and gradually decreasingexercise load. Both QT and RR intervals gradually approached the minimalvalues at about a peak exercise load (peak heart rate ˜120 beat/min) andthen gradually returned to levels that were slightly lower than theirinitial pre-exercise rest values. The evolution of QT and RR intervalswas well approximated by exponential fitting curves shown in gray inpanels A and B. The ranges for the QT-RR interval, there-and-back, timevariations were 0.34s-0.27 s-0.33 s (an average rate of change ˜0.005s/min) and 0.79 s-0.47 s-0.67 s (an average rate of change ˜0.032 s/minor ˜6 beat/min) for QT and RR intervals, respectively. The standardroot-mean-square deviation, σ, of the observed QT and RR intervals,shown by black dots in both panels, from their exponential fits were onan order of magnitude smaller than the average difference between thecorresponding peak and rest values during the entire test. Thesedeviations were σ˜0.003 s for QT and σ˜0.03 s for RR intervals,respectively. According to FIG. 9 (panels C, D) such smallperturbations, when associated with abrupt heart rate changes due tophysiological fluctuations or due to discontinuity in an exercise load,may develop and decay faster than in 10s, the time that is 60 timesshorter then the duration of one gradual (ascending or descending) stageof the exercise protocol. Such a significant difference between theamplitudes and time constants of the QT/RR interval gradual changes andabrupt heart rate fluctuations allows one to average these fluctuationsover time and fit the QT/RR protocol duration dynamics by an appropriatesmooth exponential-like function with a high order of accuracy. Asimultaneous fitting procedure (panels A, B) determines an algorithm ofa parametrical time dependence elimination from both measured QT/RR datasets and allows one to consider QT interval for each exercise stage as amonotonic function.

Based on the above-described experiment a definition for a gradual, or“quasi-stationary” exercise (or stimulation) protocol, can bequantitatively specified: A quasi-stationary exercise (or stimulation)protocol refers to two contiguous stages (each stage 3, 5 or 8 minutesor longer in duration) of gradually increasing and gradually decreasingexercise loads or stimulation, such as:

1. Each stage's duration is approximately an order of magnitude (e.g.,at least about ten times) longer than the average duration (˜1 minute)of a heart rate adjustment during an abrupt stop of the exercise betweenaverage peak load rate (120-150 beat/min) and average rest (50-70beat/min) heart rate values.

2. The standard root-mean-square deviations of the original QT/RRinterval data set from their smooth and monotonic (for each stage) fitsare of an order of magnitude (e.g., at least about ten times) smallerthan the average differences between peak and rest QT/RR interval valuesmeasured during the entire exercise under the quasi-stationary protocol.

As shown above (FIG. 10) a gradual quasi-stationary protocol itselfallows one to substantially eliminate abrupt time dependent fluctuationsfrom measured QT/RR interval data sets because these fluctuations haveshort durations and small amplitudes. Their effect can be even furtherreduced by fitting each RR/QT interval data set corresponding to eachstage with a monotonic function of time. As a result the fitted QTinterval values during each exercise stage can be presented as asubstantially monotonic and smooth function of the quasi-stationaryvarying RR interval value. Presented on the (RR-interval,QT-interval)-plane this function gives rise to a loop, whose shape, areaand other measures depend only weakly on the details of thequasi-stationary protocol, and is quite similar to the hysteresis looppresented in FIG. 2. Similar to a generic hysteresis loop, this loop canbe considered as primarily representing electrical conduction propertiesof cardiac muscle.

It is well known that exercise-induced ischemia alters conditions forcardiac electrical conduction. If a particular individual has anexercise-induced ischemic event, then one can expect that the twoexperimental composite dispersion-restitution curves corresponding tothe ascending and descending stages of the quasi-stationary protocolwill be different and will form a specific quasi-stationary hysteresisloop. Since according to a quasi-stationary protocol the evolution ofthe average values of QT and RR intervals occurs quite slowly ascompared with the rate of the transients due tosympathetic/parasympathetic and hormonal control, the hysteresis looppractically does not depend on the peculiarities of the transients. Inthat case such a hysteresis can provide an excellent measure of gradualischemic exercise dependent changes in cardiac electrical conduction andcan reflect cardiac health itself and cardiovascular system health ingeneral.

It should be particularly emphasized that neither J. Sarma et al, supra,nor A. Krahn's et al. supra, report work based on collectingquasi-stationary dependences, which are similar to the QT- interval -RRinterval dependence, since in fact both studies were designed fordifferent purposes. To the contrary, they were intentionally based onnon-quasi-stationary exercise protocols that contained an abruptexercise stop at or near the peak of the exercise load. These protocolsgenerated a different type of QT/RR interval hysteresis loop with asubstantial presence of non-stationary sympatho-adrenal transients (seeFIG. 9 above). Thus these prior art examples did not and could notinclude data which would characterize gradual changes in the dispersionand restitution properties of cardiac electrical conduction, andtherefore included no substantial indication that could be attributed toexercise-induced ischemia.

The foregoing is illustrative of the present invention and is not to beconstrued as limiting thereof. The invention is defined by the followingclaims, with equivalents of the claims to be included therein.

That which is claimed is:
 1. A method of assessing cardiac ischemia in asubject to provide a measure of cardiovascular health in said subjectduring stimulation in said subject, said method comprising the steps of:(a) collecting a first QT- and RR-interval data set from said subjectduring a stage of gradually increasing heart rate; (b) collecting asecond QT- and RR-interval data set from said subject during a stage ofgradually decreasing heart rate, with said first and second QT- andRR-interval data sets being collected while minimizing the influence ofrapid transients due to autonomic nervous system and hormonal control onsaid data sets; (c) comparing said first QT- and RR-interval data set tosaid second QT- and RR-interval data set to determine the differencebetween said data sets; and (d) generating from said comparison of step(c) a measure of cardiac ischemia during stimulation in said subject,wherein a greater said difference between said first and second datasets indicates greater cardiac ischemia and lesser cardiovascular healthin said subject.
 2. A method according to claim 1, comprising collectingsaid first and second QT- and RR-interval data sets underquasi-stationary conditions.
 3. A method according to claim 1, whereinsaid stage of gradually increasing heart rate and said stage ofgradually decreasing heart rate are each at least 3 minutes in duration.4. A method according to claim 1, wherein said stage of graduallyincreasing heart rate and said stage of gradually decreasing heart rateare together carried out for a total time of from 6 minutes to 40minutes.
 5. A method according to claim 1, wherein: both said stage ofgradually increasing heart rate and said stage of gradually decreasingheart rate are carried out between a peak rate and a minimum rate; andsaid peak rates of both said stage of gradually increasing heart rateand said stage of gradually decreasing heart rate are the same.
 6. Amethod according to claim 5, wherein: said minimum rates of both saidstage of gradually increasing heart rate and said stage of graduallydecreasing heart rate are substantially the same.
 7. A method accordingto claim 1, comprising gradually decreasing said heart rate at at leastthree different heart-rate stimulation levels.
 8. A method according toclaim 7, comprising gradually increasing said heart rate at at leastthree different heart-rate stimulation levels.
 9. A method according toclaim 1, comprising gradually increasing said heart rate and graduallydecreasing said heart rate sequentially in time.
 10. A method accordingto claim 1, comprising gradually increasing said heart rate andgradually decreasing said heart rate separately in time.
 11. A methodaccording to claim 1, wherein said generating step is carried out bygenerating curves from each of said data sets.
 12. A method according toclaim 11, wherein said generating step is carried out by comparing theshapes of said curves from said data sets.
 13. A method according toclaim 11, wherein said generating step is carried out by determining ameasure of a domain between said curves.
 14. A method according to claim11, wherein said generating step is carried out by both comparing theshapes of said curves from said data sets and determining a measure of adomain between said curves.
 15. A method according to claim 11, furthercomprising the step of displaying said curves.
 16. A method according toclaim 1, wherein said heart rate during said stage of graduallyincreasing heart rate does not exceed more than 120 beats per minute.17. A method according to claim 1, wherein said heart rate during saidstage of gradually increasing heart rate exceeds 120 beats per minute.18. A method according to claim 1, further comprising the step of: (e)comparing said measure of cardiac ischemia during stimulation to atleast one reference value; and then (f) generating from said comparisonof step (e) a quantitative indicium of cardiovascular health for saidsubject.
 19. A method according to claim 18, further comprising thesteps of: (g) treating said subject with a cardiovascular therapy; andthen (h) repeating steps (a) through (f) to assess the efficacy of saidcardiovascular therapy, in which a decrease in the difference betweensaid data sets from before said therapy to after said therapy indicatesan improvement in cardiac health in said subject from saidcardiovascular therapy.
 20. A method according to claim 19, wherein saidcardiovascular therapy is selected from the group consisting of aerobicexercise, muscle strength building, change in diet, nutritionalsupplement, weight loss, stress reduction, smoking cessation,pharmaceutical treatment, surgical treatment, and combinations thereof.21. A method according to claim 18, further comprising the step ofassessing the likelihood that said subject is at risk to experience afuture cardiac incident from said quantitative indicium.
 22. A method ofassessing cardiac ischemia in a subject to provide a measure ofcardiovascular health in that subject, said method comprising the stepsof: (a) collecting a first QT- and RR-interval data set from saidsubject during a stage of gradually increasing exercise load andgradually increasing heart rate; and then, without an intervening reststage, (b) collecting a second QT- and RR-interval data set from saidsubject during a stage of gradually decreasing exercise load andgradually decreasing heart rate; (c) comparing said first QT- andRR-interval data set to said second QT- and RR-interval data set todetermine the difference between said data sets; and (d) generating fromsaid comparison of step (c) a measure of cardiac ischemia duringexercise in said subject, wherein a greater said difference between saidfirst and second data sets indicates greater cardiac ischemia and lessercardiovascular health in said subject.
 23. A method according to claim22, wherein said stage of gradually increasing exercise load andgradually decreasing exercise load are each at least 3 minutes induration.
 24. A method according to claim 22, wherein said stage ofgradually increasing exercise load and said stage of graduallydecreasing exercise load are together carried out for a total time offrom 6 minutes to 40 minutes.
 25. A method according to claim 22,wherein: both said stage of gradually increasing exercise load and saidstage of gradually decreasing exercise load are carried out between apeak load and a minimum load; and said peak loads of both said stage ofgradually increasing exercise load and said stage of graduallydecreasing exercise load are essentially the same.
 26. A methodaccording to claim 25, wherein: said minimum loads of both said stage ofgradually increasing exercise load and said stage of graduallydecreasing exercise load are essentially the same.
 27. A methodaccording to claim 22, comprising gradually decreasing said exerciseload at at least three different load levels.
 28. A method according toclaim 22, comprising gradually increasing said exercise load at leastthree different load levels.
 29. A method according to claim 22,comprising gradually increasing said exercise load and graduallydecreasing said exercise load sequentially in time.
 30. A methodaccording to claim 22, comprising gradually increasing said exerciseload and gradually decreasing said exercise load separately in time. 31.A method according to claim 22, comprising generating curves from eachof said data sets.
 32. A method according to claim 31, wherein saidgenerating step is carried out by comparing the shapes of said curvesfrom said data sets.
 33. A method according to claim 31, wherein saidgenerating step is carried out by determining a measure of a domainbetween said curves.
 34. A method according to claim 31, wherein saidgenerating step is carried out by both comparing the shapes of saidcurves from said data sets and determining a measure of a domain betweensaid curves.
 35. A method according to claim 31, further comprising thestep of displaying said curves.
 36. A method according to claim 22,wherein said heart rate during said stage of gradually increasingexercise load does not exceed more than 120 beats per minute.
 37. Amethod according to claim 22, wherein said heart rate during said stageof gradually increasing heart rate exceeds 120 beats per minute.
 38. Amethod according to claim 22, further comprising the step of: (e)comparing said measure of cardiac ischemia during exercise to at leastone reference value; and then (f) generating from said comparison ofstep (e) a quantitative indicium of cardiovascular health for saidsubject.
 39. A method according to claim 38, further comprising thesteps of: (g) treating said subject with a cardiovascular therapy; andthen (h) repeating steps (a) through (f) to assess the efficacy of saidcardiovascular therapy, in which a decrease in the difference betweensaid data sets from before said therapy to after said therapy indicatesan improvement in cardiac health in said subject from saidcardiovascular therapy.
 40. A method according to claim 39, wherein saidcardiovascular therapy is selected from the group consisting of aerobicexercise, muscle strength building, change in diet, nutritionalsupplement, weight loss, stress reduction, smoking cessation,pharmaceutical treatment, surgical treatment, and combinations thereof.41. A method according to claim 38, further comprising the step ofassessing the likelihood that said subject is at risk to experience afuture cardiac incident from said quantitative indicium.
 42. A method ofassessing cardiac ischemia in a subject to provide a measure ofcardiovascular health in said subject, said method comprising the stepsof: (a) collecting a first QT- and RR-interval data set from saidsubject during a stage of gradually increasing exercise load andgradually increasing heart rate at least 5 minutes in duration, and atat least three different load levels; and then, without an interveningrest stage, (b) collecting a second QT- and RR-interval data set fromsaid subject during a stage of gradually decreasing exercise load andgradually decreasing heart rate at least 5 minutes in duration, and atat least three different load levels; (c) comparing said first QT- andRR-interval data set to said second QT- and RR-interval data set todetermine the difference between said data sets; (d) generating fromsaid comparison of step (c) a measure of cardiac ischemia duringexercise in said subject, wherein a greater said difference between saidfirst and second data sets indicates greater cardiac ischemia and lessercardiovascular health in said subject; (e) comparing said measure ofcardiac ischemia during exercise to at least one reference value; andthen (f) generating from said comparison of step (e) a quantitativeindicium of cardiovascular health for said subject.
 43. A methodaccording to claim 42, wherein said stage of gradually increasingexercise load and said stage of gradually decreasing exercise load aretogether carried out for a total time of from 6 minutes to 40 minutes.44. A method according to claim 42, wherein: both said stage ofgradually increasing exercise load and said stage of graduallydecreasing exercise load are carried out between a peak load and aminimum load; and said peak loads of both said stage of graduallyincreasing exercise load and said stage of gradually decreasing exerciseload are essentially the same.
 45. A method according to claim 44,wherein: said minimum loads of both said stage of gradually increasingexercise load and said stage of gradually decreasing exercise load areessentially the same.
 46. A method according to claim 42, comprisinggradually increasing said exercise load and gradually decreasing saidexercise load sequentially and contiguously in time.
 47. A methodaccording to claim 42, comprising gradually increasing said exerciseload and gradually decreasing said exercise load separately in time. 48.A method according to claim 42, wherein said generating step is carriedout by generating curves from each of said data sets.
 49. A methodaccording to claim 48, wherein said generating step is carried out bycomparing the shapes of said curves from said data sets.
 50. A methodaccording to claim 48, wherein said generating step is carried out bydetermining a measure of a domain between said curves.
 51. A methodaccording to claim 48, wherein said generating step is carried out byboth comparing the shapes of said curves from said data sets anddetermining a measure of a domain between said curves.
 52. A methodaccording to claim 48, further comprising the step of displaying saidcurves.
 53. A method according to claim 42, wherein said heart rateduring said stage of gradually increasing exercise load does not exceedmore than 120 beats per minute.
 54. A method according to claim 42,wherein said heart rate during said stage of gradually increasing heartrate exceeds 120 beats per minute.
 55. A method according to claim 42,further comprising the steps of: (g) treating said subject with acardiovascular therapy; and then (h) repeating steps (a) through (f) toassess the efficacy of said cardiovascular therapy, in which a decreasein the difference between said data sets from before said therapy toafter said therapy indicates an improvement in cardiac health in saidsubject from said cardiovascular therapy.
 56. A method according toclaim 55, wherein said cardiovascular therapy is selected from the groupconsisting of aerobic exercise, muscle strength building, change indiet, nutritional supplement, weight loss, stress reduction, smokingcessation, pharmaceutical treatment, surgical treatment, andcombinations thereof.
 57. A method according to claim 42, furthercomprising the step of assessing the likelihood that said subject is atrisk to experience a future cardiac incident from said quantitativeindicium.
 58. A method of assessing cardiac ischemia in a subject toprovide a measure of cardiovascular health in said subject duringstimulation in said subject, said method comprising the steps of: (a)collecting a first QT- and RR-interval data set from said subject duringa stage of gradually increasing heart rate, said heart rate beinggradually increased in response to actual heart rate data collected fromconcurrent monitoring of said patient; (b) collecting a second QT- andRR-interval data set from said subject during a stage of graduallydecreasing heart rate, said heart rate being gradually decreased inresponse to actual heart rate data collected from concurrent monitoringof said patient; (c) comparing said first QT- and RR-interval data setto said second QT- and RR-interval data set to determine the differencebetween said data sets; and (d) generating from said comparison of step(c) a measure of cardiac ischemia during stimulation in said subject,wherein a greater said difference between said first and second datasets indicates greater cardiac ischemia and lesser cardiovascular healthin said subject.
 59. A method according to claim 58, wherein said firstand second QT- and RR-interval data sets are collected without anintervening rest period.
 60. A method according to claim 58, whereinsaid stage of gradually increasing heart rate and gradually decreasingheart rate are each at least 3 minutes in duration.
 61. A methodaccording to claim 58, wherein said stage of gradually increasing heartrate and said stage of gradually decreasing heart rate are togethercarried out for a total time of from 6 minutes to 40 minutes.
 62. Amethod according to claim 58, wherein: both said stage of graduallyincreasing heart rate and said stage of gradually decreasing heart rateare carried out between a peak rate and a minimum rate; and said peakrates of both said stage of gradually increasing heart rate and saidstage of gradually decreasing heart rate are substantially the same. 63.A method according to claim 62, wherein: said minimum rates of both saidstage of gradually increasing heart rate and said stage of graduallydecreasing heart rate are the same.
 64. A method according to claim 58,comprising gradually decreasing said heart rate at at least threedifferent heart-rate stimulation levels.
 65. A method according to claim64, comprising gradually increasing said heart rate at at least threedifferent heart-rate stimulation levels.
 66. A method according to claim58, comprising gradually increasing said heart rate and graduallydecreasing said heart rate sequentially in time.
 67. A method accordingto claim 58, comprising gradually increasing heart rate and graduallydecreasing said heart rate separately in time.
 68. A method according toclaim 58, wherein said generating step is carried out by generatingcurves from each of said data sets.
 69. A method according to claim 68,wherein said generating step is carried out by comparing the shapes ofsaid curves from said data sets.
 70. A method according to claim 68,wherein said generating step is carried out by determining a measure ofa domain between said curves.
 71. A method according to claim 68,wherein said generating step is carried out by both comparing the shapesof said curves from said data sets and determining a measure of a domainbetween said curves.
 72. A method according to claim 68, furthercomprising the step of displaying said curves.
 73. A method according toclaim 58, wherein said heart rate during said stage of graduallyincreasing heart rate does not exceed more than 120 beats per minute.74. A method according to claim 58, wherein said heart rate during saidstage of gradually increasing heart rate exceeds 120 beats per minute.75. A method according to claim 58, further comprising the step of: (e)comparing said measure of cardiac ischemia during stimulation to atleast one reference value; and then (f) generating from said comparisonof step (e) a quantitative indicium of cardiovascular health for saidsubject.
 76. A method according to claim 75, further comprising thesteps of: (g) treating said subject with a cardiovascular therapy; andthen (h) repeating steps (a) through (f) to assess the efficacy of saidcardiovascular therapy, in which a decrease in the difference betweensaid data sets from before said therapy to after said therapy indicatesan improvement in cardiac health in said subject from saidcardiovascular therapy.
 77. A method according to claim 76, wherein saidcardiovascular therapy is selected from the group consisting of aerobicexercise, muscle strength building, change in diet, nutritionalsupplement, weight loss, stress reduction, smoking cessation,pharmaceutical treatment, surgical treatment, and combinations thereof.78. A method according to claim 75, further comprising the step ofassessing the likelihood that said subject is at risk to experience afuture cardiac incident from said quantitative indicium.